HA Surface Presented Yeast Flu Vaccine and Its Enhancement by CD154 Codisplay

HA Surface 展示酵母流感疫苗及其 CD154 Codisplay 增强版

• 批准号: 7883273
• 负责人: KAIMING YE
• 金额: $ 31.32万
• 依托单位: UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-07 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883273
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adjuvant; Adopted; Adverse effects; Affect; Allergic Reaction; Animal Experiments; Animals; Antibiotics; Antibodies; Antigen-Presenting Cells; Antigens; Antiviral Agents; Avian Influenza; Avian Influenza A Virus; Biological; Biological Assay; Biological Models; Bird Flu vaccine; Body Weight decreased; Bone Marrow; Breathing; CD80 gene; CD8B1 gene; Cancer Vaccines; Cell Culture Techniques; Cell Wall; Cell membrane; Cell surface; Cells; Cessation of life; Chickens; Clinical Trials; Containment; Culture Media; Dendritic Cells; Development; Disease; Disease Outbreaks; Disulfides; Dose; Extracellular Matrix; Figs - dietary; Flow Cytometry; Fluorescence Microscopy; Glucans; Goals; HIV vaccine; Hand; Hemagglutinin; Hepatitis B Vaccines; Histocompatibility Antigens Class II; Human; Hypersensitivity; Hypotension; ICAM1 gene; IgG1; Immune; Immune response; Immune system; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; Immunologic Adjuvants; Inbred BALB C Mice; Incubated; Influenza; Influenza A Virus, H5N1 Subtype; Interferon Type II; Interleukin-12; Lipopolysaccharides; Malignant Neoplasms; Mammalian Cell; Masks; Measures; Mediating; Membrane Proteins; Methodology; Methods; Mus; Pharmaceutical Preparations; Population; Preparation; Production; Protein Binding; Proteins; Public Health; Recombinants; Refrigeration; Reporting; Route; Safety; Seeds; Serum; Societies; Subunit Vaccines; Surface; Survival Rate; System; T cell response; TNFRSF5 gene; TNFSF5 gene; Techniques; Technology; Test Result; Testing; Time; Tissue Sample; Translating; United States; Urticaria; Vaccinated; Vaccination; Vaccine Production; Vaccines; Variant; Viral Proteins; Virus; Virus Diseases; Western Blotting; Work; Yeasts; base; cell mediated immune response; combat; cost; dosage; economic impact; egg; enzyme linked immunospot assay; flu; glycosylation; immunogenic; immunogenicity; influenza virus strain; influenza virus vaccine; influenzavirus; interest; large scale production; new technology; pandemic disease; pandemic influenza; preclinical study; prevent; public health relevance; receptor; research study; response; vaccine development; vaccine efficacy; yeast protein

DESCRIPTION (provided by applicant): Vaccination is currently the only method that can effectively impede the spread of influenza viruses among people. Traditional egg-based influenza vaccine technologies suffer from their incapability of massive and rapid production of vaccines against circulating influenza if a global outbreak occurs. Here, a new type of potent influenza vaccines is proposed based on the PI's previous works on protein surface display. The core of this new technology is to display a viral protein such as avian influenza H5N1 hemagglutinin (HA) on yeast surface in a manner such that these recombinant yeasts can serve as vaccines against influenza. Yeast is known of being able to express functional HA. The surface display of HA can significantly facilitate the recognition of antigens by host immune systems and mediate an immunoadjuvant effect with yeast cell membrane components. Although yeast has different glycosylation capability as compared to mammalian cells, this limited glycosylation may actually be a benefit to formulating a yeast vaccine. It has been reported that the glycosylation of natural influenza viruses in humans and in the standard vaccine actually interferes with induction of immunity by preventing access of antibodies to the HA surface. This benefit will be investigated thoroughly in this work. Alternatively, glycosylated yeast will be employed to construct HA surface-displayed yeast vaccines for evaluating the alteration of immunity of these vaccines. To enhance the efficacy and immunogenicity of the yeast vaccines, a dual-protein surface display technique will be adopted to codisplay the HA with CD154. The codisplay of HA with CD154 will further stimulate the maturation of antigen presenting cells and promote the adaptive immune response. Taken together, a hypothesis was developed that HA surface-displayed yeast vaccines can elicit strong and protective immunity against influenza. Furthermore, these potent vaccines can be enhanced by co-displaying HA with CD154. A recent animal vaccination study conducted in PI's lab supports this hypothesis. This project is proposed to further verify this hypothesis, three aims are proposed: Aim 1, Generate HA surface presented yeast influenza vaccines; Aim 2, Characterize both humoral and cell-mediated immune responses induced by yeast vaccines in animals (mice); Aim 3, Demonstrate the protection of mice from lethal avian influenza using yeast vaccines. The long-term goals of this project are to translate the animal studies into preclinical studies, determine the immunogenicity of these yeast vaccines in humans, and to augment this technology to develop other vaccines for treating many virus- infection related diseases such as AIDS and cancers. Unlike virus-based vaccines, yeast vaccines are safe for use in humans, and vaccine storage does not require refrigeration. Moreover, they can be massively and rapidly produced at a low cost. In addition, these vaccines do not require the passage of virus through eggs, offering a possibility for vaccine seed strain development that more closely matches the original "wild" virus and translating potentially into a better immunogenic and effective response. PUBLIC HEALTH RELEVANCE: In the absence of any control measures (vaccination or drugs), it has been estimated that in the United States a 3medium2level4 pandemic could affect between 15% and 35% of the U.S. Population, and the economic impact could range between $71 and $167 billion. The proposed technology advances vaccine production technology, which can be used for massive and rapid manufacturing not only avian influenza vaccines but also other vaccines such as cancer vaccines. Thus, this technology has the potential to impact broadly on our ability to treat and prevent virus-related diseases, stating with innumerable potential society benefits and large commercial potential.

描述（由申请人提供）：疫苗接种是目前唯一可以有效阻碍流感病毒在人们中传播的方法。如果发生全球疫情，传统的基于卵的流感疫苗技术遭受了其无能为力和快速生产疫苗与循环流感的能力。在这里，提出了一种新型的有效流感疫苗，该疫苗是根据PI先前在蛋白质表面显示的作品的。这项新技术的核心是在酵母表面上展示病毒蛋白，例如禽流感H5N1血凝集素（HA），以使这些重组酵母菌可以用作抗流感的疫苗。酵母众所周知能够表达功能性HA。 HA的表面显示可以显着促进宿主免疫系统对抗原的识别，并用酵母细胞膜成分介导免疫辅助作用。尽管与哺乳动物细胞相比，酵母具有不同的糖基化能力，但这种有限的糖基化实际上可能是配制酵母菌疫苗的好处。据报道，人类和标准疫苗中天然流感病毒的糖基化实际上会通过防止抗体进入HA表面诱导免疫。这项工作将对这一好处进行彻底调查。或者，将采用糖基化的酵母来构建HA表面播放的酵母疫苗，以评估这些疫苗免疫的改变。为了增强酵母疫苗的功效和免疫原性，将采用双蛋白表面显示技术来用CD154进行编码。 HA与CD154的编码将进一步刺激抗原呈递细胞的成熟并促进适应性免疫反应。综上所述，提出了一个假设，即HA表面播放的酵母菌疫苗可以引起对流感的强烈保护和保护性免疫。此外，可以通过与CD154共同播放HA来增强这些有效的疫苗。在PI实验室中进行的一项最近的动物疫苗接种研究支持了这一假设。提出了该项目以进一步验证这一假设，提出了三个目标：目标1，产生HA表面呈现出酵母流感疫苗； AIM 2，表征动物（小鼠）酵母疫苗引起的体液和细胞介导的免疫反应； AIM 3，使用酵母疫苗证明了对小鼠免受致命禽流感的保护。该项目的长期目标是将动物研究转化为临床前研究，确定这些酵母菌疫苗在人类中的免疫原性，并增强该技术以开发其他疫苗，以治疗许多与病毒感染相关的疾病，例如艾滋病和癌症。与基于病毒的疫苗不同，酵母菌疫苗可安全用于人类，疫苗储存不需要制冷。此外，它们可以以低成本大规模和快速生产。此外，这些疫苗不需要病毒通过卵，提供了疫苗种子菌株发育的可能性，该疫苗可能与原始的“野生”病毒相匹配，并可能转化为更好的免疫原性和有效反应。公共卫生相关性：在没有任何控制措施（疫苗接种或药物）的情况下，据估计，在美国，3Medium2level4大流行可能影响美国人口的15％至35％，经济影响可能在71至1670亿美元之间。拟议的技术推进了疫苗生产技术，可用于大规模和快速生产，不仅是禽流感疫苗，还可用于癌症疫苗等其他疫苗。因此，该技术有可能对我们治疗和预防与病毒相关疾病的能力广泛影响，并表明无数的潜在社会利益和巨大的商业潜力。